Hemostasis

The prevention of blood loss from a damaged blood vessel is referred to as hemostasis. Three inherent mechanisms contribute to hemostasis:

• Vascular constriction

• Formation of platelet plug

• Blood coagulation

Vascular constriction. The first mechanism to occur is vascular constriction. Immediately after a blood vessel is cut or severed, the vascular smooth muscle automatically constricts. This results in a decrease in the flow of blood through the vessel that helps to limit blood loss. The vasoconstriction is caused by several factors:

• Sympathetic nerve reflexes in response to pain

• Local myogenic vasospasm in response to injury

• Locally produced vasoconstrictors released from damaged tissue and from platelets

When the extent of the trauma to the vessel is increased, the degree of vascular constriction is increased. Accordingly, a sharply cut blood vessel bleeds far more profusely than a blood vessel damaged by a more crushing injury. The vasoconstriction may last for many minutes or hours, thus providing time for the two subsequent mechanisms to develop and get under way.

Formation of a platelet plug. The formation of a platelet plug physically blocks small holes in blood vessels. Normally, platelets are unable to adhere to the endothelial lining of the blood vessels. The surface of the platelets contains a coat of glycoproteins that repels the normal endothelium. Interestingly, these same glycoproteins enable the platelets to adhere to damaged vessels. When platelets come into contact with a damaged vascular surface, in particular collagen fibers in the vessel wall or damaged endothelial cells, the platelets become activated. These platelets become "sticky" and adhere to the damaged tissue. They also release ADP and thromboxane A2, a prostaglandin metabolite, which enhance the stickiness of other platelets. Consequently, more and more platelets adhere to the damaged vessel, ultimately forming a plug. This process is also referred to as agglutination. Furthermore, thromboxane A2, as well as serotonin (also released from the platelets), contributes to the initial mechanism of vasoconstriction.

Pharmacy application: antiplatelet drugs

Platelets play a role in each of the mechanisms of normal he-mostasis: vasoconstriction, formation of the platelet plug, and blood coagulation. However, they are also involved in pathological processes that lead to atherosclerosis and thrombosis (formation of a blood clot within the vascular system). Antiplatelet drugs interfere with platelet function and are used to prevent the development of atherosclerosis and formation of arterial thrombi.

The prototype of antiplatelet drugs is aspirin, which inhibits cyclooxygenase, an enzyme involved in arachidonic acid metabolism. Inhibition of cyclooxygenase blocks the synthesis of throm-boxane A2, the platelet product that promotes vasoconstriction and platelet aggregation. Because platelets are simply cell fragments, they are incapable of synthesizing new proteins, including enzymes. Therefore, aspirin-induced inhibition of cyclooxygenase is permanent and lasts for the life of the platelet (7 to 10 days).

Aspirin is maximally effective as an antithrombotic agent at the comparatively low dose of 81 to 325 mg per day. (The antipyretic dose of aspirin in adults is 325 to 650 mg every 4 h.) Higher doses of aspirin are actually contraindicated in patients prone to thromboembolism. At higher doses, aspirin also reduces synthesis of prostacyclin, another arachidonic acid metabolite. Prostacyclin normally inhibits platelet aggregation. The prophylactic administration of low-dose aspirin has been shown to increase survival following myocardial infarction, decrease incidence of stroke, and assist in maintenance of patency of coronary bypass grafts.

Blood coagulation. The third major step in hemostasis is coagulation, or the formation of a blood clot. This complex process involves a series of reactions that result in formation of a protein fiber meshwork that stabilizes the platelet plug. Three essential steps lead to clotting (see Figure 16.1):

• Activation of factor X

• Conversion of prothrombin into thrombin

• Conversion of fibrinogen into fibrin

All together, 12 clotting factors are in the plasma. These factors, which are proteins synthesized in the liver, are normally found circulating in plasma

CONTACT WITH COLLAGEN OR FOREIGN SURFACE

Inactive factor XII ■

Inactive factor XI

Active factor XII (Hageman factor)

Inactive factor IX

Active factor XI

Ca++ factor IV Active factor IX

Ca++ factor VIII PF3

INTRINSIC MECHANISM

Inactive factor X

TISSUE DAMAGE

►Tissue thromboplasti

Ca++ factor VII

Active factor X

EXTRINSIC MECHANISM

Prothrombin ||-

Ca++ factor V PF3

Fibrinogin^l—Fibrin threads!

Factor XIII

Stabilized fibrin meshwork

BLOOD CLOT

Figure 16.1 Coagulation pathways. Blood coagulation may be elicited by two mechanisms occurring independently or, more often, concurrently. The intrinsic mechanism begins when blood comes into contact with the collagen in a damaged vessel wall or with a foreign surface (e.g., test tube). This causes the activation of factor XII, or Hageman factor, followed by activation of other clotting factors and, finally, factor X. The extrinsic mechanism occurs when damaged tissue releases tissue thrombo-plastin; this mechanism activates factor X directly. Activation of factor X leads to the conversion of prothrombin into thrombin. Thrombin then leads to the conversion of fibrinogen into fibrin threads. The fibrin forms the stabilized meshwork that traps blood cells and forms the blood clot (PF3, platelet factor 3).

in their inactive forms. Activation of one of these factors leads to activation of another factor, and so on, resulting in a cascade of reactions culminating in fibrin formation.

Activated factor X, along with Ca++ ion, factor V, and PF3 (collectively referred to as the prothrombin activator), catalyzes the conversion of prothrombin into thrombin. Thrombin then catalyzes the conversion of fibrinogen into fibrin, an insoluble, thread-like polymer. The fibrin threads form a meshwork that traps blood cells, platelets, and plasma to form the blood clot. The clotting cascade may be elicited by means of two mechanisms (see Figure 16.1):

• Extrinsic mechanism

• Intrinsic mechanism

The extrinsic mechanism of blood coagulation begins when a blood vessel is ruptured and the surrounding tissues are damaged. The traumatized tissue releases a complex of substances referred to as tissue thromboplastin. The tissue thromboplastin further complexes with factor VII and Ca++ ions to activate factor X directly.

The intrinsic mechanism of blood coagulation causes the blood to clot within the vessel. It is activated when the blood is traumatized or when it comes into contact with the exposed collagen of a damaged vessel wall. This contact activates factor XII (Hageman factor) in the blood. Simultaneously, platelets are activated, so they begin adhering to the collagen in the vessel wall to form the platelet plug. In addition to ADP and thromboxane A2, these aggregated platelets also release PF3. This substance plays a role in subsequent clotting reactions. (It is important to note at this point that platelets are involved in all three mechanisms of hemostasis: vascular constriction, formation of the platelet plugs, and blood coagulation.)

Activated factor XII leads to the activation of factor XI; in turn, activated factor XI, along with Ca++ ions and factor IV, leads to activation of factor IX. Activated factor IX, along with Ca++ ions, factor VIII, and PF3, leads to the activation of factor X. From the point of factor X activation, the extrinsic and intrinsic mechanisms follow the same pathway to fibrin formation.

The extrinsic and intrinsic mechanisms typically occur simultaneously. The extrinsic mechanism coagulates the blood that has escaped into the tissue prior to the sealing of the vessel. The intrinsic mechanism coagulates the blood within the damaged vessel. Another important difference involves the speed at which these two mechanisms cause coagulation. Because the extrinsic mechanism causes activation of factor X directly, clotting begins within seconds. The intrinsic mechanism is much slower, usually requiring 1 to 6 min to form a clot. However, the cascade of reactions characteristic of this mechanism allows for amplification. Each molecule of activated clotting factor may activate many molecules of the clotting factor in the next step of the cascade. Therefore, a few molecules of activated Hageman factor can lead to activation of hundreds of molecules of factor X and a very powerful coagulation response.

Once the clot is formed, the platelets trapped within it contract, shrinking the fibrin meshwork. This clot retraction pulls the edges of the damaged vessel closer together. Blood coagulation is limited to the site of damage. Once the blood clotting factors have carried out their activities, they are rapidly inactivated by enzymes present in plasma and surrounding tissue.

• Activates factor XIII, which strengthens and stabilizes the fibrin meshwork of the clot

Clot dissolution. Once the blood vessel has been repaired, the clots must be removed in order to prevent permanent obstruction. Plasmin is a proteolytic enzyme that digests fibrin. It is synthesized from its precursor, plasminogen. The conversion of plasminogen into plasmin involves several substances, including factor XII (Hageman factor), that are also involved in the coagulation cascade. Within a few days after the blood has clotted, enough plasmin has been formed to dissolve the clot. The residue of the clot dissolution is removed by the phagocytic white blood cells (neutrophils and macrophages).

Prevention of blood clotting in the normal vascular system. Several factors contribute to the prevention of blood clotting in the normal vascular system:

• Smoothness of the endothelial lining prevents contact activation of the intrinsic mechanism.

• A layer of glycocalyx on the endothelium repels clotting factors and platelets.

• Thrombomodulin is a protein on the endothelium that (1) binds with thrombin, reducing its availability for the clotting process; and (2) activates protein C, which acts as an anticoagulant by inactivating factors V and VIII.

Anticoagulant drugs include heparin and warfarin (Coumadin®) —agents used to prevent deep vein thrombosis. They are also used to prevent formation of emboli due to atrial fibrillation, valvular heart disease, and other cardiac disorders. Heparin, which is not absorbed by the gastrointestinal tract, is available only by injection; its effect is immediate.

The most commonly used oral anticoagulant drug in the U.S. is warfarin. It acts by altering vitamin K so that it is unavailable to participate in synthesis of vitamin K-dependent coagulation factors in the liver (coagulation factors II, VII, IX, and X). Because of the presence of preformed clotting factors in the blood, the full antithrombotic effect of warfarin therapy may require 36 to 72 h.

The major adverse effect of warfarin is bleeding. (Ironically, this compound was originally introduced as a very effective ro-denticide. As the active ingredient in rodent poison, it causes death due to internal hemorrhaging.) Furthermore, because it readily crosses the placenta and can cause a hemorrhagic disorder in the fetus, it is contraindicated in pregnant women.

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.